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1.
Hum Mol Genet ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31600786

RESUMO

We previously identified five SNPs at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate 2 loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5,662 cases and 9,237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF]=0.40) was associated with DLBCL risk (OR=0.83, P=3.62x10-13). rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5,510 cases and 12,817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF=0.45) was also associated with DLBCL risk (OR=1.20, P=2.31x10-12). This SNP is 29,426 bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.

2.
Blood ; 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31420334

RESUMO

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30,234 VTE cases and 172,122 controls and assessed the association between 12,923,718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new, independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for both novel and previously known regions co-localized with eQTL signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

3.
Am J Epidemiol ; 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31364705

RESUMO

In this study, we identified plasma metabolites associated with habitual physical activity among 5197 U.S. participants from the Nurses' Health Study (NHS), NHSII, and the Health Professional Follow-up Study (HPFS). Physical activity was assessed every 2-4 years by self-reported questionnaires. Blood was collected in the NHS between 1989-1990, NHSII during 1996-1999, and the HPFS during 1993-1995. Metabolic profiling was conducted by liquid chromatography-mass spectrometry (LC-MS). Our study included 337 known metabolites, with 256 of them classified as lipids. We corrected for multiple testing by controlling the tail probability of the proportion of false positives (TPPFP) and accounted for correlated tests using bootstrapping. We independently replicated the identified metabolites among 2305 women in the Women's Health Initiative (WHI) in 1993. After adjusting for multiple variables including body mass index, physical activity was significantly associated with 20 metabolites after correcting for multiple testing (TPPFP<0.05). Specifically, physical activity was positively associated with two amino acids (citrulline and glycine), four cholesteryl esters [CEs] (C18:2, C18:1, C16:0, and C18:3), eight phosphocholines [PCs] and lysophosphatidylcholines [LPCs] (C36:4 PC-A, C34:3 PC plasmalogen, C36:3 PC plasmalogen, C34:2 PC plasmalogen, C36:2 PC, C18:2 LPC, C20:5 LPC, and C18:1 LPC), and three phosphatidylethanolamines [PEs] and lysophosphatidylethanolamines [LPEs] (C18:2 LPE, C18:1 LPE, and C38:3 PE plasmalogen). Half of the identified metabolites were replicated in the WHI. Our study may help identify biomarkers of physical activity and provide insight into biological mechanisms underlying the beneficial effect of being physically active on cardiometabolic health.

4.
Circ Cardiovasc Qual Outcomes ; 12(4): e005284, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30909729

RESUMO

BACKGROUND: Empirical data on the link between stress and cardiovascular disease (CVD) risk among black women is limited. We examined associations of stressful life events and social strain with incident CVD among black women and tested for effect modification by resilience. METHODS AND RESULTS: Our analysis included 10 785 black women enrolled in the Women's Health Initiative Observational Study and Clinical Trials cohort. Participants were followed for CVD for up to 23 years (mean, 12.5). Multivariable Cox regression was used to estimate hazard ratios and 95% CIs for associations between stress-related exposures and incident CVD. We included interactions between follow-up time (age) and stressful life events because of evidence of nonproportional hazards. Effect modification by resilience was examined in the sub-cohort of 2765 women with resilience and stressful life events measures. Higher stressful life events were associated with incident CVD at ages 55 (hazard ratio for highest versus lowest quartile=1.80; 95% CI, 1.27-2.54) and 65 (hazard ratio for highest versus lowest quartile=1.40; 95% CI, 1.16-1.68), but not at older ages. Adjustment for CVD risk factors attenuated these associations. Similar associations were observed for social strain. In the sub-cohort of women with updated stressful life events and resilience measures, higher stressful life events were associated with incident CVD in multivariable-adjusted models (hazard ratio=1.61; 95% CI, 1.04-2.51). Resilience did not modify this association nor was resilience independently associated with incident CVD. CONCLUSIONS: In this cohort of older black women, recent reports of stressful life events were related to incident CVD. Resilience was unrelated to incident CVD. CLINICAL TRIALS REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00000611.

5.
Am J Prev Med ; 56(5): 664-672, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30902564

RESUMO

INTRODUCTION: Physical activity guidelines recommend minimum thresholds. This study sought to identify evidence-based thresholds to maintain disability-free status over 4years among adults with lower extremity joint symptoms. METHODS: Prospective multisite Osteoarthritis Initiative accelerometer monitoring cohort data from September 2008 through December 2014 were analyzed. Adults (n=1,564) aged ≥49years at elevated disability risk because of lower extremity joint symptoms were analyzed for biennial assessments of disability-free status from gait speed ≥1meter/second (mobility disability-free) and self-report of no limitations in activities of daily living (activities of daily living disability-free). Classification tree analyses conducted in 2017-2018 identified optimal thresholds across candidate activity intensities (sedentary, light, moderate-vigorous, total light and moderate-vigorous activity, and moderate-vigorous accrued in bouts lasting ≥10 minutes). RESULTS: Minimal thresholds of 56 and 55 moderate-vigorous minutes/week best predicted disability-free status over 4years from mobility and activities of daily living disabilities, respectively, across the candidate measures. Thresholds were consistent across sex, BMI, age, and knee osteoarthritis presence. Mobility disability onset was one eighth as frequent (3% vs 24%, RR=0.14, 95% CI=0.09, 0.20) and activities of daily living disability onset was almost half (12% vs 23%, RR=0.55, 95% CI=0.44, 0.70) among people above versus below the minimum threshold. CONCLUSIONS: Attaining an evidence-based threshold of approximately 1-hour moderate-vigorous activity/week significantly increased the likelihood of maintaining disability-free status over 4years. This minimum threshold tied to maintaining independent living abilities has value as an intermediate goal to motivate adults to take action towards the many health benefits of a physically active lifestyle.

6.
Clin Rheumatol ; 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30417223

RESUMO

OBJECTIVE: Validation of a symptom measure for early knee OA may help identify new treatments and modifiable risk factors. Symptom measures that consider pain in the context of activity level may provide better discrimination than pain alone. Therefore, we aimed to compare sensitivity to change for radiographic progression between Ambulation Adjusted Score for Knee pain (AASK), which accounts for self-reported ambulation, and Western Ontario McMaster Osteoarthritis (WOMAC) knee pain score. DESIGN: Participants were assessed annually up to 48 months using WOMAC, Physical Activity Scale for the Elderly (PASE) ambulation, and knee radiographs. AASK was defined as ((WOMAC pain) + 1)/((average daily hours of walking) + 1). Radiographs were scored for Kellgren-Lawrence (KL) grade. Linear regression, stratified by OA status, evaluated relationships between changes in AASK and WOMAC pain and KL grade over time. RESULTS: For 4191 people (8030 knees), the mean age was 61.2 (+ 9.2) years old and BMI was 28.6 (+ 4.8) kg/m2; 58% female. Over 40% of knees had WOMAC pain scores of 0; by design, no knees had AASK scores of 0. Annual changes in AASK were more sensitive to changes in KL than changes in WOMAC in those without baseline OA (0.20 and 0.16 change per unit KL change, p = 0.005 and 0.070 respectively), but performed similarly in knees with OA. CONCLUSION: AASK is simple to assess using existing validated questionnaires. AASK performs well in individuals with and without OA and should be considered in clinical trials and observational studies of early knee OA.

7.
J Bone Miner Res ; 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30461066

RESUMO

Sleep disturbances are common and may influence falls and fracture directly by influencing bone turnover and muscle strength or indirectly through high comorbidity or poor physical function. To investigate the association between self-reported sleep and falls and fractures, we prospectively studied 157,306 women in the Women's Health Initiative (WHI) using information on sleep quality, sleep duration, and insomnia from questionnaires. Annual self-report of falling two or more times (ie, "recurrent falling") during each year of follow-up was modeled with repeated measures logistic regression models fit by generalized estimating equations. Cox proportional hazards models were used to investigate sleep disturbance and time to first fracture. We examined the risks of recurrent falls and fracture by sleep duration with 7 hours as referent. We examined the risks across categories of sleep disturbance, insomnia status, and sleep quality. The average follow-up time was 7.6 years for falls and 12.0 years for fractures. In multivariable adjusted models, including adjustment for comorbidity, medications, and physical function, women who were short (≤5 hours) and long (≥10 hours) sleepers had increased odds of recurrent falls (odds ratio [OR] 1.28; 95% confidence interval [CI], 1.23 to 1.34 and OR 1.25; 95% CI, 1.09 to 1.43, respectively). Poor sleep quality, insomnia, and more sleep disturbances were also associated with an increased odds of recurrent falls. Short sleep was associated with an increased risk of all fractures, and upper limb, lower limb, and central body fractures, but not hip fractures, with hazard ratios ranging from 1.10 to 1.13 (p < 0.05). There was little association between other sleep characteristics and fracture. In conclusion, short and long sleep duration and poor sleep quality were independently associated with increased odds of recurrent falls. Short sleep was associated with modest increase in fractures. Future long-term trials of sleep interventions should include falls and fractures as endpoints. © 2018 American Society for Bone and Mineral Research.

8.
Am J Ophthalmol ; 195: 110-120, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30081016

RESUMO

PURPOSE: We conducted a secondary analysis of a randomized, placebo-controlled trial to test if hormone therapy (HT) altered the risk of open-angle glaucoma (OAG), and if the risk reduction varied by race. DESIGN: Secondary analysis of randomized controlled trial data. METHODS: We linked Medicare claims data to 25 535 women in the Women's Health Initiative. Women without a uterus were randomized to receive either oral conjugated equine estrogens (CEE 0.625 mg/day) or placebo, and women with a uterus received oral CEE and medroxyprogesterone acetate (CEE 0.625 mg/day + MPA 2.5 mg/day) or placebo. We used Cox proportional hazards models to calculate hazard ratios (HR) and 95% confidence interval. RESULTS: After exclusion of women with prevalent glaucoma or without claims for eye care provider visits, the final analysis included 8102 women (mean age = 68.5 ± 4.8 years). The OAG incidence was 7.6% (mean follow-up = 11.5 ± 5.2 years; mean HT duration = 4.4 ± 2.3 years). Increased age (P trend = .01) and African-American race (HR = 2.69, 95% CI = 2.13-3.42; white as a reference) were significant risk factors for incident OAG. We found no overall benefit of HT in reducing incident OAG (HR = 1.01, 95% CI = 0.79-1.29 in the CEE trial, and HR = 1.05, 95% CI = 0.85-1.29 in the CEE + MPA trial). However, race modified the relationship between CEE use and OAG risk (P interaction = .01), and risk was reduced in African-American women treated with CEE (HR = 0.49, 95% CI = 0.27-0.88), compared to placebo. Race did not modify the relation between CEE + MPA use and OAG risk (P interaction = .68). CONCLUSIONS: Analysis suggests that HT containing estrogen, but not a combination of estrogen and progesterone, reduces the risk of incident OAG among African-American women. Further investigation is needed.

9.
Clin Lymphoma Myeloma Leuk ; 18(9): 597-602.e1, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30049515

RESUMO

BACKGROUND: Multiple myeloma (MM) is a disease of aging adults resulting in osteolytic and/or osteoporotic bone disease. Primary osteoporosis is also highly prevalent in aging adults and is associated with increased mortality. It is unknown how concurrent osteoporosis is associated with outcomes in patients who develop MM. PATIENTS AND METHODS: We identified 362 women with MM of the 161,808 enrolled in the Women's Health Initiative (WHI) dataset and evaluated bone health using the Fracture Risk Assessment Tool (FRAX) to identify clinical factors that affect overall MM survival in post-menopausal women, as measured from the time of diagnosis. RESULTS: Of the 362 participants who developed incident MM, with an average 10.5 years of follow-up, 226 died, including 71 with high FRAX scores and 155 with low FRAX scores. On average, women with high FRAX scores were 8.3 years older at enrollment (95% confidence interval [CI], 7.2-9.3 years) and 8.0 years older at time of MM diagnosis (95% CI, 7.0-9.2 years) compared with those with low FRAX scores. MM mortality for women with high FRAX scores was greater (covariate-adjusted hazard ratio scores [aHR] 1.51; 95% CI, 1.01-2.25; P = .044) compared with those with low FRAX scores. CONCLUSION: Higher fracture risk, measured by FRAX, was associated with higher MM mortality in post-menopausal women, independent of many other clinical factors.

10.
J Bone Miner Res ; 33(7): 1199-1208, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29923225

RESUMO

Current guidelines recommend that serum C-terminal telopeptide of type I collagen (CTX) and serum procollagen type 1 aminoterminal propeptide (PINP), measured by standardized assays, be used as reference markers in observational and interventional studies. However, there are limited data to determine whether serum CTX and PINP are associated with hip fracture risk among postmenopausal women. We determined the associations of serum CTX and serum PINP with hip fracture risk among postmenopausal women aged 50 to 79 years at baseline. We performed a prospective case-control study (400 cases, 400 controls) nested in the Women's Health Initiative Observational Study, which enrolled participants at 40 US clinical centers. Cases were women with incident hip fracture not taking osteoporosis medication; hip fractures were confirmed using medical records. Untreated controls were matched by age, race/ethnicity, and date of blood sampling. Serum CTX and serum PINP were analyzed on 12-hour fasting blood samples. The main outcome measure was incident hip fracture risk (mean follow-up 7.13 years). After adjustment for body mass index, smoking, frequency of falls, history of fracture, calcium and vitamin D intake, and other relevant covariates, neither serum CTX level nor serum PINP level was statistically significantly associated with hip fracture risk (CTX ptrend = 0.22, PINP ptrend = 0.53). Our results do not support the utility of serum CTX level or PINP level to predict hip fracture risk in women in this age group. These results will inform future guidelines regarding the potential utility of these markers in fracture prediction. © 2018 American Society for Bone and Mineral Research.

11.
Circ Genom Precis Med ; 11(5): e001663, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29752399

RESUMO

BACKGROUND: Genetic variants at the SCN5A/SCN10A locus are strongly associated with electrocardiographic PR and QRS intervals. While SCN5A is the canonical cardiac sodium channel gene, the role of SCN10A in cardiac conduction is less well characterized. METHODS: We sequenced the SCN10A locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue. We explored the biophysical effect of variation on channel function using cellular electrophysiology. RESULTS: We identified 2 intronic single nucleotide polymorphisms in high linkage disequilibrium (r 2=0.86) with each other to be the strongest signals for PR (rs10428132, ß=-4.74, P=1.52×10-14) and QRS intervals (rs6599251, QRS ß=-0.73; P=1.2×10-4), respectively. Although these variants were not associated with SCN5A or SCN10A expression in human atrial tissue (n=490), they were in high linkage disequilibrium (r 2≥0.72) with a common SCN10A missense variant, rs6795970 (V1073A). In total, we identified 7 missense variants, 4 of which (I962V, P1045T, V1073A, and L1092P) were associated with cardiac conduction. These 4 missense variants cluster in the cytoplasmic linker of the second and third domains of the SCN10A protein and together form 6 common haplotypes. Using cellular electrophysiology, we found that haplotypes associated with shorter PR intervals had a significantly larger percentage of late current compared with wild-type (I962V+V1073A+L1092P, 20.2±3.3%, P=0.03, and I962V+V1073A, 22.4±0.8%, P=0.0004 versus wild-type 11.7±1.6%), and the haplotype associated with the longest PR interval had a significantly smaller late current percentage (P1045T, 6.4±1.2%, P=0.03). CONCLUSIONS: Our findings suggest an association between genetic variation in SCN10A, the late sodium current, and alterations in cardiac conduction.

12.
Clin Rheumatol ; 37(9): 2497-2504, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29728929

RESUMO

Higher levels of moderate to vigorous physical activity improve all-cause mortality and cardiovascular events. However, the effect of running, a moderate to vigorous activity, in those with knee osteoarthritis (OA), a common arthritis that occurs with aging, a high-risk group for mortality and cardiovascular events, is unclear. Therefore, we aimed to evaluate the association of self-selected running on OA symptom and structure progression in people with knee OA. This nested cohort study within the Osteoarthritis Initiative (OAI) (2004-2014) included those at least 50 years old with OA in at least one knee. Runners were defined using a self-administered questionnaire at the 96-month visit. At baseline and 48-months, symptoms were assessed and radiographs were scored for Kellgren-Lawrence (KL) grade (2-4) and medial Joint Space Narrowing (JSN) score (0-3). We evaluated the association of self-selected running with outcomes: KL worsening, medial JSN worsening, new knee pain, and improved knee pain over 48 months, adjusting for baseline age, sex, body mass index (BMI), KL score, contralateral KL score, contralateral knee pain, and injury. If data were not available at the 48-month visit, then they were imputed from the 36-month visit. One thousand two hundred three participants had a mean age of 63.2 (7.9) years, BMI of 29.5 (4.6) kg/m2, 45.3% male, and 11.5% runners. Data from 8% of participants required imputation. Adjusted odds ratios for KL grade worsening and new frequent knee pain were 0.9 (0.6-1.3) and 0.9 (0.6-1.6) respectively. Adjusted odds ratio for frequent knee pain resolution was 1.7 (1.0-2.8). Among individuals 50 years old and older with knee OA, self-selected running is associated with improved knee pain and not with worsening knee pain or radiographically defined structural progression. Therefore, self-selected running, which is likely influenced by knee symptoms and may result in lower intensity and shorter duration sessions of exercise, need not be discouraged in people with knee OA.

14.
Semin Arthritis Rheum ; 48(2): 155-161, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29449014

RESUMO

OBJECTIVE: Osteoarthritis (OA) is a disease with a substantial public health burden. Quantitative assessments of periarticular bone may be a biomarker capable of monitoring early disease progression. The purpose of this study was to evaluate whether measures of periarticular bone associate with longitudinal structural progression. METHODS: We conducted a 12-18 months longitudinal study using the Osteoarthritis Initiative (OAI). Participants received knee dual-energy x-ray absorptiometry (DXA), trabecular magnetic resonance (MR) imaging, and x-rays. Knee DXAs generated proximal tibial medial:lateral periarticular bone mineral density (paBMD) measures. Proximal tibial trabecular MR images were assessed for trabecular morphometry: apparent bone volume fraction (BVF), trabecular number, thickness, and spacing. Weight-bearing x-rays were assessed for medial tibiofemoral joint space narrowing (JSN). Chi-squared analyses assessed whether periarticular bone measures were predictive of worsening medial tibiofemoral JSN, adjusted for age, sex, and BMI. RESULTS: In all, 444 participants, mean age 64.2 ± 9.2 years, BMI 29.5 ± 4.6kg/m2, and 52% male at baseline. Medial JSN (radiographic progression) occurred in 40 participants (9%). Higher baseline medial:lateral paBMD, apparent BVF, trabecular number and thickness, and lower baseline and decreased trabecular spacing were all associated with more progression of JSN in the medial compartment. From lowest to highest baseline medial:lateral paBMD quartile groups, 2%, 5%, 11%, and 18% had medial JSN progression, respectively, between the 36- and 48-month visits, p-values = 0.001 and 0.002 unadjusted and adjusted. The rate of change in medial:lateral paBMD, apparent BVF, and spacing were associated with more medial JSN. For rate of medial:lateral paBMD change from lowest to highest quartile, the proportion of each group that experienced medial JSN progression were 5%, 5%, 11%, and 18%, with an unadjusted and adjusted p-value of 0.005. CONCLUSION: Baseline and most rates of periarticular bone change associate with knee OA structural progression, highlighting the close relationship between subchondral bone and JSN. Future studies should focus on developing these measures as predictive and pathophysiological biomarkers, and evaluating their deployment in clinical trials testing bone-targeted therapeutics.

15.
Stroke ; 49(3): 543-548, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29438084

RESUMO

BACKGROUND AND PURPOSE: Although depression is a risk factor for stroke in large prospective studies, it is unknown whether these conditions have a shared genetic basis. METHODS: We applied a polygenic risk score (PRS) for major depressive disorder derived from European ancestry analyses by the Psychiatric Genomics Consortium to a genome-wide association study of ischemic stroke in the Stroke Genetics Network of National Institute of Neurological Disorders and Stroke. Included in separate analyses were 12 577 stroke cases and 25 643 controls of European ancestry and 1353 cases and 2383 controls of African ancestry. We examined the association between depression PRS and ischemic stroke overall and with pathogenic subtypes using logistic regression analyses. RESULTS: The depression PRS was associated with higher risk of ischemic stroke overall in both European (P=0.025) and African ancestry (P=0.011) samples from the Stroke Genetics Network. Ischemic stroke risk increased by 3.0% (odds ratio, 1.03; 95% confidence interval, 1.00-1.05) for every 1 SD increase in PRS for those of European ancestry and by 8% (odds ratio, 1.08; 95% confidence interval, 1.04-1.13) for those of African ancestry. Among stroke subtypes, elevated risk of small artery occlusion was observed in both European and African ancestry samples. Depression PRS was also associated with higher risk of cardioembolic stroke in European ancestry and large artery atherosclerosis in African ancestry persons. CONCLUSIONS: Higher polygenic risk for major depressive disorder is associated with increased risk of ischemic stroke overall and with small artery occlusion. Additional associations with ischemic stroke subtypes differed by ancestry.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Depressão/genética , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Herança Multifatorial , Acidente Vascular Cerebral/genética , Idoso , Idoso de 80 Anos ou mais , Depressão/etnologia , Depressão/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/etnologia
16.
Am J Hum Genet ; 102(1): 88-102, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29304378

RESUMO

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.

17.
Lupus Sci Med ; 4(1): e000187, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29214033

RESUMO

Objective: Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genome-wide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. Methods: GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data were pooled in a random-effects meta-analysis. Results: Among the 28 SLE-related SNPs investigated, the two most convincingly associated with risk of DLBCL included the CD40 SLE risk allele rs4810485 on chromosome 20q13 (OR per risk allele=1.09, 95% CI 1.02 to 1.16, p=0.0134), and the HLA SLE risk allele rs1270942 on chromosome 6p21.33 (OR per risk allele=1.17, 95% CI 1.01 to 1.36, p=0.0362). Of additional possible interest were rs2205960 and rs12537284. The rs2205960 SNP, related to a cytokine of the tumour necrosis factor superfamily TNFSF4, was associated with an OR per risk allele of 1.07, 95% CI 1.00 to 1.16, p=0.0549. The OR for the rs12537284 (chromosome 7q32, IRF5 gene) risk allele was 1.08, 95% CI 0.99 to 1.18, p=0.0765. Conclusions: These data suggest several plausible genetic links between DLBCL and SLE.

18.
Cancer Epidemiol ; 51: 62-67, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29049937

RESUMO

BACKGROUND: The majority of women diagnosed with endometrial cancer (EC) have low cancer-specific mortality; however, a high prevalence of cardiovascular disease (CVD) risk factors places EC patients at high risk of developing CVD. In the Women's Health Initiative (WHI), we assessed the hypothesis that CVD risk was higher among women who developed EC compared with women who did not develop EC. METHODS: We compared the incidence of fatal and non-fatal CVD events among 1,179 women who developed Type I EC, 211 women who developed Type II EC, and 92,217 women who did not develop EC. We first estimated univariable cause-specific hazard ratios (CHRs) and 95% confidence intervals (CIs) for the association between an EC diagnosis (overall and by EC type) with CVD risk using Cox proportional hazards regression. Potential confounders were examined using a risk factor modeling approach; final multivariable-adjusted models included covariates that changed univariable CHRs for EC diagnosis by≥5%. RESULTS: In multivariable-adjusted models, CVD risk did not significantly differ between women who developed EC compared to women who did not develop EC (CHR=1.01, 95% CI=0.87-1.16), particularly for the subgroup of women who developed Type I EC (CHR=0.98, 95% CI=0.84-1.14); however, there was a positive but statistically nonsignificant association for Type II EC (CHR=1.32, 95% CI=0.88-1.97). CONCLUSION: Despite our null findings, women with EC should still receive counseling and support to make lifestyle changes aimed at reducing weight as appropriate, given the high prevalence of CVD risk factors at diagnosis.


Assuntos
Doenças Cardiovasculares/epidemiologia , Neoplasias do Endométrio/complicações , Saúde da Mulher/tendências , Idoso , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/patologia , Neoplasias do Endométrio/mortalidade , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Fatores de Risco , Análise de Sobrevida
19.
J Rheumatol ; 44(11): 1652-1658, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28916551

RESUMO

OBJECTIVE: The etiology of knee osteoarthritis (OA), the most common form of arthritis, is complex and may differ by race or ethnicity. In recent years, genetic studies have identified many genetic variants associated with OA, but nearly all the studies were conducted in European whites and Asian Americans. Few studies have focused on the genetics of knee OA in African Americans. METHODS: We performed a genome-wide association study of radiographic knee OA in 1217 African Americans from 2 North American cohort studies: 590 subjects from the Johnston County Osteoarthritis Project and 627 subjects from the Osteoarthritis Initiative. Analyses were conducted in each cohort separately and combined in an inverse variance fixed effects metaanalysis, which were then included in pathway analyses. We additionally tested 12 single-nucleotide polymorphisms robustly associated with OA in European white populations for association in African Americans. RESULTS: We identified a genome-wide significant variant in LINC01006 (minor allele frequency 12%; p = 4.11 × 10-9) that is less common in European white populations (minor allele frequency < 3%). Five other independent loci reached suggestive significance (p < 1 × 10-6). In pathway analyses, dorsal/ventral neural tube patterning and iron ion transport pathways were significantly associated with knee OA in African Americans (false discovery rate < 0.05). We found no evidence that previously reported OA susceptibility variants in European whites were associated with knee OA in African Americans. CONCLUSION: These results highlight differences in the genetic architecture of knee OA between African American and European whites. This finding underscores the need to include more diverse populations in OA genetics studies.


Assuntos
Afro-Americanos/genética , Articulação do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/genética , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética , Idoso , Alelos , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/diagnóstico por imagem , Tomografia Computadorizada por Raios X
20.
JAMA ; 318(10): 927-938, 2017 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-28898378

RESUMO

Importance: Health outcomes from the Women's Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials have been reported, but previous publications have generally not focused on all-cause and cause-specific mortality. Objective: To examine total and cause-specific cumulative mortality, including during the intervention and extended postintervention follow-up, of the 2 Women's Health Initiative hormone therapy trials. Design, Setting, and Participants: Observational follow-up of US multiethnic postmenopausal women aged 50 to 79 years enrolled in 2 randomized clinical trials between 1993 and 1998 and followed up through December 31, 2014. Interventions: Conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n = 8506) vs placebo (n = 8102) for 5.6 years (median) or CEE alone (n = 5310) vs placebo (n = 5429) for 7.2 years (median). Main Outcomes and Measures: All-cause mortality (primary outcome) and cause-specific mortality (cardiovascular disease mortality, cancer mortality, and other major causes of mortality) in the 2 trials pooled and in each trial individually, with prespecified analyses by 10-year age group based on age at time of randomization. Results: Among 27 347 women who were randomized (baseline mean [SD] age, 63.4 [7.2] years; 80.6% white), mortality follow-up was available for more than 98%. During the cumulative 18-year follow-up, 7489 deaths occurred (1088 deaths during the intervention phase and 6401 deaths during postintervention follow-up). All-cause mortality was 27.1% in the hormone therapy group vs 27.6% in the placebo group (hazard ratio [HR], 0.99 [95% CI, 0.94-1.03]) in the overall pooled cohort; with CEE plus MPA, the HR was 1.02 (95% CI, 0.96-1.08); and with CEE alone, the HR was 0.94 (95% CI, 0.88-1.01). In the pooled cohort for cardiovascular mortality, the HR was 1.00 (95% CI, 0.92-1.08 [8.9 % with hormone therapy vs 9.0% with placebo]); for total cancer mortality, the HR was 1.03 (95% CI, 0.95-1.12 [8.2 % with hormone therapy vs 8.0% with placebo]); and for other causes, the HR was 0.95 (95% CI, 0.88-1.02 [10.0% with hormone therapy vs 10.7% with placebo]), and results did not differ significantly between trials. When examined by 10-year age groups comparing younger women (aged 50-59 years) to older women (aged 70-79 years) in the pooled cohort, the ratio of nominal HRs for all-cause mortality was 0.61 (95% CI, 0.43-0.87) during the intervention phase and the ratio was 0.87 (95% CI, 0.76-1.00) during cumulative 18-year follow-up, without significant heterogeneity between trials. Conclusions and Relevance: Among postmenopausal women, hormone therapy with CEE plus MPA for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years. Trial Registration: clinicaltrials.gov Identifier: NCT00000611.


Assuntos
Terapia de Reposição de Estrogênios , Estrogênios Conjugados (USP)/uso terapêutico , Medroxiprogesterona/uso terapêutico , Mortalidade , Idoso , Doenças Cardiovasculares/mortalidade , Causas de Morte , Método Duplo-Cego , Terapia de Reposição de Estrogênios/efeitos adversos , Estrogênios Conjugados (USP)/efeitos adversos , Feminino , Seguimentos , Humanos , Medroxiprogesterona/efeitos adversos , Pessoa de Meia-Idade , Neoplasias/mortalidade , Pós-Menopausa , Risco
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